S221: BORTEZOMIB TO R-DHAP COMPARED TO R-DHAP IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA ELIGIBLE TO STEM CELL TRANPLANTATION: FINAL RESULTS OF PHASE II RANDOMIZED FIL-VERAL12
Authors: A. Chiappella, M. Balzarotti, B Botto, A. Castiglione, F. Cavallo, S. V. Usai, M. Zanni, C. Califano, F. Re, C. Ghiggi, A. Olivieri, P. Corradini, A. M. Liberati, S. Volpetti, M. G. Michieli, A Tucci, G. Gaidano, M. Tani, F. Ciambelli, G. Musuraca, D. Vallisa, F. Merli, A. L. Molinari, A. Tafuri, V. R. Zilioli, D. Marino, C. Stelitano, S. A. Pileri, G. Ciccone, U. Vitolo
Journal: HemaSphere (2022)

Background: The standard treatment in patients with diffuse large-B cell lymphoma (DLBCL) relapsed/refractory (R/R) after first line therapy is a cisplatin-containing regimen followed by consolidation with high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) in responsive ones after induction. Bortezomib had proven activity in aggressive lymphomas. Aims: On these bases, the Fondazione Italiana Linfomi designed the FIL-VERAL12 trial, aimed at evaluating whether the addition of bortezomib to rituximab-cisplatin-cytarabine-dexametasone (BR-DHAP) increases complete response rate (CR, according to Lugano 2007 criteria) prior auto-SCT compared to standard R-DHAP. Methods: FIL-VERAL12 was a prospective, multicenter, two-arm randomized phase II trial (NCT01805557).The primary study endpoint was CR after 4 courses of R-DHAP or BR-DHAP, assuming a 30% CR for the standard arm and a 50% CR in experimental arm. Inclusion criteria were: patients aged 18-65 years eligible to high-dose therapy, with R/R DLBCL after first line chemoimmunotherapy. Patients were stratified by relapsed or refractory and randomized 1:1 to receive: a) the standard salvage therapy R-DHAP every 28 days for 4 cycles and b) subcutaneous 1.5 mg/ms bortezomib on days 1 and 4 of each 4-week cycle in addition to the same regimen. Results: From January 2013 to November 2018, 114 patients were screened, and 107 patients that fulfilled the inclusion criteria were enrolled into the trial and randomized to receive R-DHAP or BR-DHAP (54 patients in R-DHAP, 53 in BR-DHAP). Principal clinical characteristics were: median age 57 years (IQR: 48;62); stage III/IV 83 patients (78%); International Prognostic Index (IPI) risk >2 37 (35%). All patients received rituximab and anthracycline-based regimens as first line treatment. Considering the time at relapse, 53 patients (50%) were registered as relapsed (median time at relapse 10.8 months, IQR: 6.9;20.9) and 54 (50%) as refractory (0.9 months, IQR 0.52;1.3). 52 (49%) patients completed the planned 4 cycles of therapy; 55 did not, due to progressive disease in 42, adverse events or clinician decision in 13. At the end of the 4 courses, the pre-auto-SCT response was: CR 29 (27%), Partial Response (PR) 9 (17%); according to arm of randomization, the primary end point was not met, with CR 28% for R-DHAP and 26% for BR-DHAP (p-value 0.563). Fifty patients (44%) performed a consolidation with SCT, 24 in R-DHAP arm and 26 in BR-DHAP arm; auto-SCT was performed in 39 patients and allo-SCT in 11. The addition of bortezomib to standard R-DHAP did not impact the mobilization, with a median number of CD34+ collected of 6.43 x 10^6 cells CD34/kg (IQR: 4.40;9.11) in R-DHAP and 6.78 x 10^6 cells CD34/kg (IQR: 5.00;9.68) in BR-DHAP. Sixty patients died: 49 (82%) due to lymphoma, 1 due to toxicity, 3 due to transplant related mortality, 7 due to other causes. The incidence of adverse events was similar in the two arms, with grade 3-4 haematological toxicities in 96 patients (90%), g3-4 infection in 5 (5%), g3-4 neurotoxicity in 4 (4%). At a median follow-up of 50 months, 2-years PFS was 29% (95%CI: 19.94;41.83) and 41% (27.67;53.84) for R-DHAP and BR-DHAP, respectively; HR 0.65 (0.41;1.02) p 0.062; 2-years OS was 43% (28.98;56.30) and 52% (37.80;64.56) for R-DHAP and BR-DHAP, respectively; HR 0.74 (0.44;1.23) p 0.244. Summary/Conclusion: In the FIL-VERAL12 phase II randomized trial, the addition of bortezomib to R-DHAP did not improve the CR rate pre-auto-SCT of R/R DLBCL patients eligible to high-dose chemotherapy plus SCT; a numerically higher 2-year PFS rate was observed in BR-DHAP arm.